The goal of this application is to characterize the properties and differentiation of the multipotent stem/progenitor cells in the cochlea. The mammalian inner ear uses sensory hair cells for mechanoelectric transduction of auditory stimuli and conducts this information to the brain via sensory neurons for hearing. Since the adult cochlea completely lacks this regenerative potential, damage to the sensory hair cells causes irreversible deafness, which is a condition with high prevalence worldwide affecting over 5% of the world's population and approximately one-third of people over 65 years of age. In the past several decades, scientists have developed regenerative strategies, including gene therapy intended to artificially force the inner ear to regenerate or replace lost hair cells and cell therapy to apply developmental cues involved in the generation of hair cells from murine and human ES cells. However, to date, most of these strategies have failed to induce a true post-trauma regeneration of hair cells that leads to functional recovery, and currently we do not have a definitive strategy for auditory repair and regeneration. As a full understanding of how an organ system forms is the prerequisite to finding ways to repair it when damaged, we performed unbiased clonal analysis of individual inner ear cells to address their lineage relationship. We unexpectedly discovered that the cochlea harbors a previously unknown population of multipotent stem/progenitor cells that are capable of giving rise to both sensory hair cells and surrounding supporting cells as well as to different types of cells in the spiral ganglion during not only development but also postnatal maintenance and regeneration in response to injury. Given the desperate need for novel approaches toward auditory repair strategies, our results stimulate further research into the development of new cell-based strategies for auditory regeneration and repair. In this application, we propose to perform single-cell analysis to characterize the properties and differentiation of the multipotent cochlear progenitor population. Delineating a roadmap for hair cell development has major implications for regenerative medicine as it provides critical molecular information that can be used to guide efficient differentiation of a stem-cell into a hair cell fate. !